High Throughput Screening of Medicines for Malaria Ventures Chemical Libraries to Identify Novel Inhibitors of Candida auris

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Candida species represent the most frequent etiological agents of opportunistic fungal invasive infections in an expanding spectrum of immune- and medically-compromised patients, and candidiasis now represents the third-to-fourth most frequent nosocomial infection worldwide, carrying unacceptably high mortality rates of 30-60%, which alarmingly have remained unchanged during the last three decades. Most recently, Candida auris has emerged as a multi-drug resistant opportunistic fungus around the globe, including the U.S, with a notable ability to easily spread between hospitalized patients and nursing home residents leading to major outbreaks in healthcare settings. According to data from the Centers for Disease Control and Prevention (CDC), 90% of C. auris strains in the U.S. have been resistant to fluconazole, 30% have been resistant to amphotericin B, and 5% have been resistant to echinocandins. Thus, the fact that some strains of C. auris demonstrate pan-resistance to all three major classes of clinically-used antifungals agents is particularly concerning. Indeed, in its recently released Antibiotic Resistance Threats in the United States, the CDC has designated C. auris as one of only 5 “Urgent Threats” requiring swift and aggressive action, since there is a grave concern that multi- and pan-resistant C. auris isolates will spread and become prevalent, and mostly untreatable, in the years to come. Thus, there is dire need for the development of novel therapeutics against this emerging pathogen. To conquer this formidable challenge, we propose a highly efficient approach by establishing a novel partnership between academia (our laboratory) and a non-for profit organization (Medicines for Malaria Ventures, MMV) in order to perform high throughput screening (HTS) of MMV’s chemical libraries containing 180,000 small molecule compounds to identify high value compounds with novel antifungal activity against C. auris. Although similar approaches have had a major impact in the Parasitology field, these MMV’s libraries have never before been screened for antifungal activity. To this end, we proposed the following: i) perform HTS of MMV’s chemical libraries to identify high value compounds with novel antifungal activity against C. auris, for which we will use a 384-well microtiter plate based model recently developed in our laboratory to screen MMV’s “Hit-Generation” (140K compounds) and “Diversity” (40K compounds) chemical libraries in order to identify inhibitors of C. auris growth; and ii) to characterize the leading compounds by performing a battery of in vitro tests to further establish their antifungal activity and safety/toxicity properties.